IKKβ

J Hematol Oncol.(一) 类花生酸(Eicosanoid)信号通路：二十烷基硫酸酯信号通路在生理过程和病理过程中都起着关键作用，通过类花生酸将炎症与癌症联系起来。二十碳多不饱和脂肪酸(PUFAs)是由20碳多不饱和脂肪酸(PUFAs)氧化而成的具有高度生物活性的衍生物，可通过环氧合酶(COX)、脂氧合酶(LOX)和细胞色素P450途径产生。COX途径产生前列腺素(PGs)和血栓素A(TXs)，而LOX途径则产生白三烯(LTs)和脂氧素(LXs)。COX信号通路COX家族中，COX-2的表达会受到早期炎症(proinflammatory)的上调，并被发现和调控多种肿瘤的进展相关。在炎症反应的早期阶段，COX-2衍生的PG被认为具有促炎功能。前列腺素D2、前列腺素E2、前列腺素F2α、前列腺素I2和血栓素A2是通过COX通路衍生的五种关键 PG。COX/PEG2COX-2/CSK3β信号还和上皮-间充质转化有关，通过抑制GSK3β来促进E-钙粘蛋白、β-连环蛋白和p120连环蛋白的蛋白质稳定性。抑制COX-2可以下调E-钙黏蛋白导致细胞死亡。PGE2通过其两种E-前列腺素受体EP2和EP4提供信号传导来塑造DC功能。EP4调节CD80、CD86、CD83、MHC II等激活标志物上调以及IL-10和IL-23的产生，引导cDC2成熟，促进T细胞扩增，形成抑制性而非促炎性T细胞群富集。PGE2还可能通过E2调节NK细胞合成IFN-γ来诱导免疫抑制，从而促进肿瘤的发生。肿瘤来源的前列腺素E2(PGE2)介导MDSC分化和获得促肿瘤特征。在PGE2暴露期间，EP2/4联合阻断M-MDSCs可防止这些抑制特征的发生。双重 EP2/EP4 PGE2受体拮抗剂增加了肿瘤微环境淋巴细胞浸润，并显着降低了多种肿瘤模型中的疾病负担。前列腺素D2则是COX-2的另一种代谢物，可能在慢性炎症和癌症中发挥双重作用。PGD2与其受体PTGDR2之间的相互作用抑制了胃癌细胞的自我更新，并减弱了胃癌的生长和转移。脂氧合酶(LOX)信号通路LOX通路负责将花生四烯酸代谢为白三烯，包括白三烯A4(LTA4)、LTB4和LTD4等。炎症细胞(包括白细胞、巨噬细胞和肥大细胞)是白三烯的主要来源。抑制LTB4受体可抑制炎症相关肿瘤的进展，LTD4则在肝细胞癌和慢性乙型肝炎患者的循环中上调。LOX途径主要包括5-LOX、12-LOX和15-LOX。5-LOX在上皮性癌和淋巴瘤中高度表达，具有促血管生成和促肿瘤活性。12-LOX通过激活整合素连接的激酶/NF-κB途径来促进肿瘤的生长。而15-LOX的代谢产物被发现能增强肿瘤相关炎症，既有促肿瘤作用又有抗肿瘤作用。另一种由LOX衍生的类花生酸脂毒素(lipoxins， LXs)则具有抗肿瘤作用。在前列腺癌中，LXA4通过抑制METTL3和或FPR2/IRF4途径，以促进巨噬细胞M2样极化。LXA4对炎性巨噬细胞极化的抑制作用与p-NF-κB p65和IRF5活性的下调有关，从而降低了LPS诱导的M1巨噬细胞通过FPR2/IRF5信号通路的表型和功能极化。 J Hematol Oncol.(二)JAK/STAT信号通路STAT3在炎症反应和肿瘤进展中发挥着广泛的作用。多种生长因子和细胞因子参与典型的STAT3通路，调节细胞分化、血管生成和肿瘤形成。IL-6和STAT3是启动肿瘤的肠上皮细胞生存和增殖所必需的。此外，在设计肠道的肿瘤如前列腺癌中，肠道生物失调增加了肠道通透性，肿瘤内的内毒素通过NF-κB/IL 6/STAT3轴促进了肿瘤的进展。Int Immunopharmacol.影响JAK/STAT通路的药物种类复杂，包括植物化学物质、合成药物和生物分子等等。Int Immunopharmacol.(三)金属代谢铁和ROS氧化还原铁代谢失调是肿瘤细胞的一个重要标志，在肿瘤细胞中，恶性肿瘤细胞需要大量的铁来生存和增殖。细胞色素P450酶、一氧化氮合酶、NADPH氧化酶和脂氧合酶等铁依赖性酶参与ROS的产生。同时，谷胱甘肽过氧化物酶GPX4是一种铁死亡的中枢抑制剂，GPX4利用还原性谷胱甘肽将活性的PUFA-PL-OOH还原为非活性和非致死性的PUFA-PL-OH。抑制Gpx4可通过诱导铁性死亡而增强治疗的抗肿瘤效应。十年铁死亡：双向调控与药物开发锌和NF-κB通路锌与许多炎症性细胞因子的产生和信号传递有关。当对应激刺激做出急性反应时，血浆锌浓度迅速下降。人体的锌代谢与ZIP8等锌转运蛋白的活性密切相关。在感染过程中，激活的NF-κB增加ZIP8的表达，ZIP8定位于细胞膜并调节锌的摄取。锌抑制了IKKβ的活性，从而减弱了炎症反应。参考文献：1.Wang M, Chen S, He X, Yuan Y, Wei X. Targeting inflammation as cancer therapy. J Hematol Oncol. 2024 Mar 22;17(1):13. doi: 10.1186/s13045-024-01528-7.2.Balamurugan K,et al.Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer. JCI Insight. 2023 Mar 22;8(6):e156057. doi: 10.1172/jci.insight.156057.3.Cuenca-Escalona J,et al.PGE2-EP4 signaling steers cDC2 maturation toward the induction of suppressive T-cell responses. Eur J Immunol. 2024 Mar;54(3):e2350770. doi: 10.1002/eji.202350770.4.Francica BJ,et al.Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors. Cancer Res Commun. 2023 Aug 8;3(8):1486-1500. doi: 10.1158/2767-9764.CRC-23-0249.5.Yuan J, et al. Lipoxin A4 regulates M1/M2 macrophage polarization via FPR2-IRF pathway. Inflammopharmacology. 2022 Apr;30(2):487-498. doi: 10.1007/s10787-022-00942-y.6.Wang Y,et al. Deciphering JAK/STAT signaling pathway: A multifaceted approach to tumorigenesis, progression and therapeutic interventions. Int Immunopharmacol. 2024 Mar 22;131:111846. doi: 10.1016/j.intimp.2024.111846.·····

Scientists have discovered a gene mutation is responsible for causing psoriasis -- a chronic inflammatory skin disease that causes patients to develop red, scaly and itchy patches across their body. According to researchers, if two copies of this mutated gene (known as IKBKB) are present, patients with psoriasis may go on to develop psoriatic arthritis, leaving them with joint pain, stiffness and swelling. It's hoped the findings will lead to improved diagnosis and treatment for patients with psoriasis and psoriatic arthritis -- conditions that patients say carry stigma in the community. Scientists from The Australian National University (ANU) have discovered a gene mutation is responsible for causing psoriasis -- a chronic inflammatory skin disease that causes patients to develop red, scaly and itchy patches across their body. According to ANU researcher Dr Chelisa Cardinez, if two copies of this mutated gene (known as IKBKB) are present, patients with psoriasis may go on to develop psoriatic arthritis, leaving them with joint pain, stiffness and swelling. Thanks to the world-first discovery from ANU, scientists now know what causes the progression from a skin-only disease to a skin and joint disease. It's hoped the findings will lead to improved diagnosis and treatment for patients with psoriasis and psoriatic arthritis -- conditions that patients say carry stigma in the community. "Using a mouse model, we identified that this mutation led to an abnormal function in a group of immune cells known as regulatory T cells," Dr Cardinez, from the ANU John Curtin School of Medical Research (JCSMR), said. "These cells are normally considered gatekeepers of the immune system. However, we found that this mutation alters the function of these cells, causing them to contribute to inflammation and promote the onset of disease." Rebecca Davey is one of at least 500,000 Australians that live with psoriasis. She also happens to have psoriatic arthritis and says the stiffness and pain she feels when she gets out of bed in the morning can be extreme. "People don't understand the debilitating effects these conditions can have on the individual and in fact a whole family when someone is in constant pain, has poor sleep from pain, and feels constantly fatigued," Ms Davey said. "My psoriatic arthritis drugs have largely reduced the larger outbreaks on my skin, but you do have to consider everything you put on your skin and the fabrics you wear. As a former nurse, even the constant hand washing that was required for work would cause my skin to flare up. It's one of the reasons why I no longer work in the hospital system." Psoriasis and psoriatic arthritis are forms of autoimmune disease. These types of diseases occur when the immune system attacks healthy cells after wrongly perceiving them as a threat. According to Arthritis Australia, three out of every 10 Australians with psoriasis develop psoriatic arthritis. Although there is no cure for psoriasis, there are treatments that can help manage the condition. In October 2023, the Pharmaceutical Benefits Scheme (PBS) listed a new, subsidised drug for Australians living with severe psoriasis. Ms Davey, who is also CEO of Arthritis ACT, says it's important to break down the stigma associated with these conditions. She says psoriasis is very misunderstood in the community. "So many people are accused of having poor hygiene due to the plaques or even just minor skin lesions as they erupt. It's not the individual's fault that their skin is in the condition it's in; psoriasis is a painful, debilitating condition," she said. "I had no idea what was causing my hands to flare up all the time. Our poor GPs often don't recognise these conditions early. "In regional and rural areas there is a drastic shortage of specialists both in dermatology and rheumatology to diagnose and treat these conditions, and people can wait over a year for an appointment if their symptoms are less dramatic. "We must raise greater awareness of invisible disabilities such as those created by these conditions. A person might look ok from the outside, but in reality they are struggling on a daily basis." Dr Cardinez said: "Studies have shown that delays in psoriatic arthritis diagnosis is linked to worse clinical outcomes for patients. Therefore, earlier detection and treatment of these immune diseases is key to improving health outcomes. "By developing a better understanding of the IKBKB gene and the role it plays in promoting the onset of these diseases, it could bring us a step closer to one day finding a cure, which would offer new hope for hundreds of thousands of Australians."

汉坦病毒（HTNV）经由啮齿动物传播，其感染小鼠并不致病，但感染人体可引起重症肾综合征出血热（HFRS）。HTNV感染致病机制不清是目前临床防治药物研发的瓶颈。2023年1月10日，空军军医大学张芳琳、雷迎峰、徐志凯、张西京共同通讯在Nature Communications发表题为“Disparate macrophage responses are linked to infection outcome of Hantan virus in humans or rodents”的研究论文，该研究表明鼠源及人源巨噬细胞对HTNV感染反应性的差异决定其对机体炎症的调控作用不同，与HTNV感染致病关系密切。进一步研究显示，感染早期病毒核衣壳蛋白（NP）激活Notch—NF-κB通路使得鼠源/人源巨噬细胞发生M1活化，促进炎症进展；在感染后期，人源巨噬细胞表现为持续活化，而鼠源巨噬细胞可通过Notch—Lnc-ip65—p65轴抑制p65磷酸化，避免M1持续活化而引起过度炎症反应。本研究从长非编码RNA（LncRNA）角度阐释了鼠源/人源巨噬细胞对HTNV反应性差异的分子机制，明晰了鼠源/人源巨噬细胞对HTNV反应性差异发病机制的理论依据，也为HTNV感染提供了一种特殊的治疗策略。汉坦病毒（HTNV）是在世界上分布广、传播途径多、危害极其严重的出血热病毒，感染人体可引起肾综合征出血热（HFRS），以血管内皮损伤及通透性增加为基本病理表现，发病机制与机体过度炎症反应及其产生的细胞因子风暴关系密切。但自然界中的宿主动物，如黑线姬鼠、褐家鼠等啮齿类动物感染HTNV后可以长期携带病毒但不发病，其潜在机制仍有待阐明。巨噬细胞在机体抗病毒免疫应答过程中发挥关键作用，是连接宿主固有和适应性免疫应答的桥梁，也是调控机体炎症反应、维持免疫稳态的重要因素。巨噬细胞在感染过程中存在M1和M2两种可以相互转化的活化模式，前者主要在疾病急性期发挥作用，可促进炎症发生和进展，利于病原清除但加重免疫损伤；后者主要在疾病恢复期/疾病慢性化过程中发挥作用，可抑制炎症反应、促进组织修复但不利于病原清除。本研究探究了巨噬细胞活化模式与HFRS疾病进展的关系，流式细胞术等结果显示HFRS疾病早期，M1活化比例显著增加且与疾病严重程度正相关，人源以TNF-α为核心的促炎巨噬细胞过度活化是HTNV感染所致细胞因子风暴及血管内皮功能紊乱的重要因素，鼠源巨噬细胞的促炎表型（M1）则表现为先激活后抑制。提示鼠源及人源巨噬细胞对于HTNV感染反应性的差异及其不同活化模式对炎症反应的调控作用。文章模式图（图源自Nature Communications）Notch信号是进化中高度保守的信号途径，其调控巨噬细胞活化的机制也逐步被揭示。当Notch受体受到相应配体刺激后，其胞内活化片段NICD从细胞膜内侧释放并进入核内。NICD入核后与转录因子RBP-J相互作用，从而调节基因表达。NF-κB家族中的p65是巨噬细胞活化的关键转录因子，p65-p50组成的异源二聚体活化后可以促进TNF-α、IL-6等炎性细胞因子或趋化因子产生。在感染条件下，巨噬细胞中模式识别信号活化，其通过多种方式激活IκB激酶复合物，IKK-β可促进IκB-α磷酸化并降解，解除IκB-α对p65-p50的抑制作用。本研究发现HTNV感染早期，NICD在胞浆中积累，其与p65和IKK-β相互作用促进p65磷酸化，进而促进M1活化。然而在小鼠中，NICD在感染晚期易位进入细胞核并诱导各种鼠特异性LncRNA表达。其中，Lnc-ip65与NICD竞争结合p65并抑制p65磷酸化，扭转巨噬细胞促炎表型。这些结果为汉坦病毒致病机制提供了新观点，揭示了LncRNA在阻断巨噬细胞多度炎症反应中的免疫功能，为HFRS和其他炎症性疾病提供了潜在的治疗策略。参考文献：Yi Yin Tai et al, Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension, Science Translational Medicine (2024). DOI: 10.1126/scitranslmed.add2029. www.science.org/doi/10.1126/scitranslmed.add2029责编|探索君排版|探索君文章来源|“iNature”End往期精选围观王晓红教授团队：绘制单次冷冻囊胚移植成功的女性植入期外周血microRNA动态表达谱，开拓领域创新研究热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文不孕症治疗新方向！又一导致女性不孕的关键因素被发现热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~